AUTHOR=Ke Yujun , Chen Ping , Wu Chunlan , Wang Qinqin , Zeng Kai , Liang Min 

TITLE=β2-microglobulin and cognitive decline: unraveling the mediating role of the Dunedin Pace of Aging methylation

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 17 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1505185

DOI=10.3389/fnagi.2025.1505185

ISSN=1663-4365

ABSTRACT=BackgroundProgressive cognitive decline is inevitable with aging. Growing evidence links β2-microglobulin (B2M) to aging and cognitive decline. However, the current evidence is inadequate to establish a definitive association. This study aims to investigate the relationship between B2M levels and cognitive performance, together with the mediating effect of the pace of biological aging.MethodsUtilizing the 1999–2002 National Health and Nutrition Examination Survey (NHANES) database, cognitive performance was measured via the Digit Symbol Substitution Test (DSST), while the pace of biological aging was quantified using a new generation DNA methylation algorithm, Dunedin Pace of Aging methylation (DunedinPoAm). Weighted multivariable linear regression was used to explore the relationship between B2M levels and cognitive performance. Furthermore, subgroup analysis and interaction tests were performed to assess the relationship’s stability. Mediation analysis was conducted to investigate the mediating effect of DunedinPoAm on the association between B2M levels and cognitive performance.ResultsThe study included 1,267 participants aged 60 and over. After correcting for all confounders, for each one-unit increment in log-transformed B2M levels, the DSST score fell by 5.13 points (95%CI −9.03 to −1.24), while the level of DunedinPoAm increased by 0.04 (95%CI 0.01–0.07). The analysis of the trend test yielded identical results (p for trend <0.05). Additionally, across every subgroup analyzed, the correlation between B2M levels and cognitive performance was stable (p for interaction >0.05). Further mediation analysis showed that DunedinPoAm mediated 9.0% (95%CI 0.1–43.2%) of the association between B2M and cognitive performance.ConclusionThese findings suggested a substantial link between elevated B2M levels and cognitive decline among U.S. older adults, partly mediated through the faster pace of aging. This correlation highlights the potential of B2M as a biomarker for early detection and therapeutic intervention of aging-related cognitive decline.